Application of cell-free DNA fungal polymerase chain reaction for invasive fungal disease evaluation in pediatric oncology and stem cell transplant patients.

BACKGROUND: Molecular diagnostics may enable early, noninvasive detection of invasive fungal disease (IFD) in immunocompromised patients. Cell-free deoxyribonucleic acid (cfDNA) fungal polymerase chain reaction (PCR) assays were recently incorporated into institutional prolonged febrile neutropenia pathways. We aimed to evaluate the performance of plasma cfDNA PCR panels (mold and Candida panels) in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients with clinical concern for IFD. METHODS: This single-center, observational study assessed plasma cfDNA fungal PCR performance for noninvasive IFD detection in hospitalized pediatric oncology and HSCT patients. The primary outcome was IFD diagnosis per published consensus definitions within 1 month. Positive and negative agreement between plasma cfDNA fungal PCR and consensus definitions were calculated. We also described test turnaround time and patient survival. RESULTS: From October 2021 to 2022, 54 patients underwent 60 evaluations with 11 proven/probable IFD cases. Comparing plasma cfDNA fungal PCRs to consensus definitions for proven/probable IFD, there was 73% positive agreement and 96% negative agreement. Two proven/probable cases with negative PCRs were caused by organisms not included on either panel. Median time to cfDNA fungal PCR result was 35 hours (interquartile range: 19-69) in eight proven/probable cases detected by cfDNA fungal PCR. There were 17 deaths among 54 patients, and IFD contributed to 45% of deaths in patients with proven/probable IFD. CONCLUSIONS: Plasma cfDNA fungal PCRs detected relevant molds or yeast in most cases classified as proven/probable IFD. However, this targeted approach missed some cases. More studies are required to determine optimal utilization of molecular diagnostics in pediatric patients.

Prescribing Patterns of Nonrecommended Medications for Children With Acute COVID-19.

OBJECTIVE: Repurposed medications for acute coronavirus disease 2019 (COVID-19) continued to be prescribed after results from rigorous studies and national guidelines discouraged use. We aimed to describe prescribing rates of nonrecommended medications for acute COVID-19 in children, associations with demographic factors, and provider type and specialty. METHODS: In this retrospective cohort of children <18 years in a large United States all-payer claims database, we identified prescriptions within 2 weeks of an acute COVID-19 diagnosis. We calculated prescription rate, performed multivariable logistic regression to identify risk factors, and described prescriber type and specialty during nonrecommended periods defined by national guidelines. RESULTS: We identified 3 082 626 COVID-19 diagnoses in 2 949 118 children between March 7, 2020 and December 31, 2022. Hydroxychloroquine (HCQ) and ivermectin were prescribed in 0.03% and 0.14% of COVID-19 cases, respectively, during nonrecommended periods (after September 12, 2020 for HCQ and February 5, 2021 for ivermectin) with considerable variation by state. Prescription rates were 4 times the national average in Arkansas (HCQ) and Oklahoma (ivermectin). Older age, nonpublic insurance, and emergency department or urgent care visit were associated with increased risk of either prescription. Additionally, residence in nonurban and low-income areas was associated with ivermectin prescription. General practitioners had the highest rates of prescribing. CONCLUSIONS: Although nonrecommended medication prescription rates were low, the overall COVID-19 burden translated into high numbers of ineffective and potentially harmful prescriptions. Understanding overuse patterns can help mitigate downstream consequences of misinformation. Reaching providers and parents with clear evidence-based recommendations is crucial to children's health.

Dynamics and prognostic value of plasma cell-free DNA PCR in patients with invasive aspergillosis and mucormycosis.

Aspergillus species and Mucorales agents are the primary etiologies of invasive fungal disease (IFD). Biomarkers that predict outcomes are needed to improve care. Patients diagnosed with invasive aspergillosis and mucormycosis using plasma cell-free DNA (cfDNA) PCR were retested weekly for 4 weeks. The primary outcome included all-cause mortality at 6 weeks and 6 months based on baseline cycle threshold (CT) values and results of follow-up cfDNA PCR testing. Forty-five patients with Aspergillus and 30 with invasive Mucorales infection were retested weekly for a total of 197 tests. Using the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, 30.7% (23/75), 25.3% (19/75), and 38.7% (29/75) had proven, probable, and possible IFD, respectively. In addition, 97.3% (73/75) were immunocompromised. Baseline CT increased significantly starting at week 1 for Mucorales and week 2 for Aspergillus. Aspergillosis and mucormycosis patients with higher baseline CT (CT >40 and >35, respectively) had a nonsignificantly higher survival rate at 6 weeks, compared with patients with lower baseline CT. Mucormycosis patients with higher baseline CT had a significantly higher survival rate at 6 months. Mucormycosis, but not aspergillosis patients, with repeat positive cfDNA PCR results had a nonsignificantly lower survival rate at 6 weeks and 6 months compared with patients who reverted to negative. Aspergillosis patients with baseline serum Aspergillus galactomannan index <0.5 and <1.0 had significantly higher survival rates at 6 weeks when compared with those with index ≥0.5 and ≥1.0, respectively. Baseline plasma cfDNA PCR CT can potentially be used to prognosticate survival in patients with invasive Aspergillus and Mucorales infections. IMPORTANCE: We show that Aspergillus and Mucorales plasma cell-free DNA PCR can be used not only to noninvasively diagnose patients with invasive fungal disease but also to correlate the baseline cycle threshold with survival outcomes, thus potentially allowing the identification of patients at risk for poor outcomes, who may benefit from more targeted therapies.

Guidance for prevention and management of COVID-19 in children and adolescents: A consensus statement from the Pediatric Infectious Diseases Society Pediatric COVID-19 Therapies Taskforce.

BACKGROUND: Since November 2019, the SARS-CoV-2 pandemic has created challenges for preventing and managing COVID-19 in children and adolescents. Most research to develop new therapeutic interventions or to repurpose existing ones has been undertaken in adults, and although most cases of infection in pediatric populations are mild, there have been many cases of critical and fatal infection. Understanding the risk factors for severe illness and the evidence for safety, efficacy, and effectiveness of therapies for COVID-19 in children is necessary to optimize therapy. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacology, and pediatric intensive care medicine from 21 geographically diverse North American institutions was re-convened. Through a series of teleconferences and web-based surveys and a systematic review with meta-analysis of data for risk factors, a guidance statement comprising a series of recommendations for risk stratification, treatment, and prevention of COVID-19 was developed and refined based on expert consensus. RESULTS: There are identifiable clinical characteristics that enable risk stratification for patients at risk for severe COVID-19. These risk factors can be used to guide the treatment of hospitalized and non-hospitalized children and adolescents with COVID-19 and to guide preventative therapy where options remain available.

Vaccine Effectiveness Against Long COVID in Children.

OBJECTIVES: Vaccination reduces the risk of acute coronavirus disease 2019 (COVID-19) in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5 to 17 years. METHODS: This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record program for visits after vaccine availability. We examined both probable (symptom-based) and diagnosed long COVID after vaccination. RESULTS: The vaccination rate was 67% in the cohort of 1 037 936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, whereas diagnosed long COVID was 0.8%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5-44.7) against probable long COVID and 41.7% (15.0-60.0) against diagnosed long COVID. VE was higher for adolescents (50.3% [36.6-61.0]) than children aged 5 to 11 (23.8% [4.9-39.0]). VE was higher at 6 months (61.4% [51.0-69.6]) but decreased to 10.6% (-26.8% to 37.0%) at 18-months. CONCLUSIONS: This large retrospective study shows moderate protective effect of severe acute respiratory coronavirus 2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including electronic health record sources and prospective data.

Real-World Effectiveness of BNT162b2 Against Infection and Severe Diseases in Children and Adolescents.

BACKGROUND: The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited. OBJECTIVE: To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents. DESIGN: Comparative effectiveness research accounting for underreported vaccination in 3 study cohorts: adolescents (12 to 20 years) during the Delta phase and children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. SETTING: A national collaboration of pediatric health systems (PEDSnet). PARTICIPANTS: 77 392 adolescents (45 007 vaccinated) during the Delta phase and 111 539 children (50 398 vaccinated) and 56 080 adolescents (21 180 vaccinated) during the Omicron phase. INTERVENTION: First dose of the BNT162b2 vaccine versus no receipt of COVID-19 vaccine. MEASUREMENTS: Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100, with confounders balanced via propensity score stratification. RESULTS: During the Delta period, the estimated effectiveness of the BNT162b2 vaccine was 98.4% (95% CI, 98.1% to 98.7%) against documented infection among adolescents, with no statistically significant waning after receipt of the first dose. An analysis of cardiac complications did not suggest a statistically significant difference between vaccinated and unvaccinated groups. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (CI, 72.2% to 76.2%). Higher levels of effectiveness were seen against moderate or severe COVID-19 (75.5% [CI, 69.0% to 81.0%]) and ICU admission with COVID-19 (84.9% [CI, 64.8% to 93.5%]). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (CI, 83.8% to 87.1%), with 84.8% (CI, 77.3% to 89.9%) against moderate or severe COVID-19, and 91.5% (CI, 69.5% to 97.6%) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined 4 months after the first dose and then stabilized. The analysis showed a lower risk for cardiac complications in the vaccinated group during the Omicron variant period. LIMITATION: Observational study design and potentially undocumented infection. CONCLUSION: This study suggests that BNT162b2 was effective for various COVID-19-related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time. PRIMARY FUNDING SOURCE: National Institutes of Health.

Suboptimal antimicrobial discharge prescriptions at a tertiary referral children's hospital.

Objective: To determine the rate of and factors associated with suboptimal discharge antimicrobial prescribing at a tertiary referral children's hospital. Design: Retrospective cohort. Setting: Tertiary referral children's hospital. Population: All enteral antimicrobial discharge prescriptions at Lucile Packard Children's Hospital Stanford from January 1st, 2021 through December 31st, 2021. Method: All enteral discharge antimicrobials are routinely evaluated by our antimicrobial stewardship program within 48 hours of hospital discharge. Antimicrobials are determined to be optimal or suboptimal by an antimicrobial stewardship pharmacist after evaluating the prescribed choice of antimicrobial, dose, duration, dosing frequency, and formulation. The rate and factors associated with suboptimal antimicrobial discharge prescribing were evaluated. Results: Of 2,593 antimicrobial prescriptions ordered at discharge, 19.7% were suboptimal. Suboptimal prescriptions were due to incorrect duration (72.2%), dose (31.0%), dose frequency (23.3%), drug choice (6.5%), or formulation (5.7%). In total, 87.2% of antimicrobials for perioperative prophylaxis and 13.5% of treatment antimicrobials were suboptimal. Antimicrobials with the highest rate of suboptimal prescriptions were amoxicillin-clavulanate (40.7%), clindamycin (36.6%), and cephalexin (36.6%). Conclusion: Suboptimal antimicrobial discharge prescriptions are common and present an opportunity for antimicrobial stewardship programs during hospital transition of care. Factors associated with suboptimal prescriptions differ by antimicrobial and prescribed indication, indicating that multiple stewardship interventions may be needed to improve prescribing.